The present invention relates to methods for immunizing a subject against meningococcal disease. More particularly, the invention relates to a method for avoiding immunological tolerance against meningococcal species in vaccinated subjects, using an anti-meningococcal glycoconjugate vaccine composition as the primary immunogen.
Neisseria meningitidis is an important cause of invasive bacterial disease, with an estimated 2600 cases of meningococcal meningitis occurring in the United States each year, primarily in children and young adults (Jafari et al. (1997) MMWR 46:1-10; Perkins et al. (1997) MMWR 46:13-21). In England and Wales, there has been a steady rise in reported cases of meningococcal disease since 1984, peaking at greater than 2000 cases per year in 1991 and 1992 (Jones, D. (1995) xe2x80x9cEpidemiology of Meningococcal Disease in Europe and the USA, in Meningococcal disease, Cartwright, K. (ed), John Wiley and Sons Ltd., pp. 147-157). Despite antimicrobial therapy, mortality rates in Europe and in the USA from meningococcal disease remain high (i.e., 12 to 14 percent of cases, Jafari, supra and Jones, supra.) In most industrialized countries, the vast majority of isolates causing meningococcal disease are serogroups B or C (Jones, supra; Harrison, L. (1995) JAMA 273:419-421; Jackson et al. (1995) JAMA 273:383-389; Whalen et al. (1995) JAMA 273:390-394). For reasons that are unknown, serogroup A strains, the major cause of disease in developing countries (Harrison, supra) are very rare in industrialized countries.
A substantial portion of meningococcal disease is potentially preventable by vaccination (Artenstein et al. (1970) N. Engl. J. Med. 282:417-420; Reingold et al. (1985) Lancet 2:114-118; Peltola et al. (1977) N. Engl. J. Med. 297:686-691). Effective polysaccharide vaccines against disease caused by serogroup A and C strains have been available for more than 20 years and, more recently, tetravalent vaccines have been licensed for prevention of serogroups A, C, Y and W135 isolates (Armand et al. (1982) J. Biol. Stand. 10:335-339; Arnbrosch et al. (1983) Bull. World Health Organ. 61:317-323).
Despite their general availability, meningococcal polysaccharide vaccines are used infrequently in industrialized societies (Harrison, supra). For example, in the United States, vaccination is largely limited to certain high risk situations, such as with patients with functional asplenia or terminal complement deficiency diseases (Jafari, supra). Vaccination is also used for controlling meningococcal disease in military recruits (Harrison, supra), and may be beneficial for healthy individuals traveling to hyperendemic areas, and for control of civilian outbreaks of meningococcal disease caused by serogroup strains included in the available vaccines (Perkins, supra; Masterton et al. (1988) J. Infect. 17:177-182). The reasons for the limited use of meningococcal polysaccharide vaccines in the general population include their poor immunogenicity in infants less than 2 years of age, the age group at greatest risk of developing meningococcal disease (Jafari, supra; Jones, supra) In addition, the duration of vaccine-induced protection elicited in older children and adults is limited (Zangwill et al. (1994) J. Infect. Dis. 169:847-852). Finally, these polysaccharide vaccines provide no protection against disease caused by serogroup B strains, which accounts for approximately 40% of all cases in the United States (Jafari, supra) and Canada (Whalen, supra), and an even greater proportion in the United Kingdom (Jones, supra).
More effective polysaccharide-protein conjugate vaccines for prevention of disease caused by meningococcal A and C strains are currently under development (reviewed in Granoff et al. (1997) Int. J. Infect. Dis. 1:152-157). These conjugate vaccines are immunogenic in infants and toddlers, and elicit high titers of serum bactericidal antibody (Fairley (1996) J. Infect. Dis. 174:1360-1363, and Lieberman et al. (1996) JAMA 275:1499-1503).
In addition, polysaccharide derivatives have been prepared to circumvent disease caused by meningococcal B strains. For example, C4-C8 N-acyl-substituted polysaccharide derivatives have been described. See, EP Publication No. 504,202 B, to Jennings et al. Similarly, U.S. Pat. No. 4,727,136 to Jennings et al. describes an N-propionylated meningococcal B polysaccharide molecule. Mice immunized with glycoconjugates formed with these polysaccharide derivatives were reported to elicit high titers of IgG antibodies. Jennings et al. (1986) J. Immunol. 137:1708. More recently, meningococcal B oligosaccharide derivative fragments, and glycoconjugates made from those fragments, have been shown to be highly effective immunogens for use in anti-meningococcal B vaccine preparations. International Publication No. WO 98/086543.
Although anti-meningococcal conjugate vaccine preparations are more effective than unconjugated vaccines in infants and toddlers, unconjugated polysaccharide vaccines are highly immunogenic in adults, eliciting effective short-term protection against disease (Artenstein, supra., Gold et al. (1971) Bull. World Health Organ. 45:279-282). Thus, there appears to be no real advantage to using the more costly meningococcal conjugate vaccine in adults. Indeed, in comparative immunogenicity studies, the magnitude of the serum antibody response of adults given a dose of unconjugated pneumococcal or meningococcal polysaccharide vaccine appears to be similar to that elicited by the corresponding polysaccharide-protein conjugate vaccine (Anderson et al. (1994) Infect. Immun. 62:3391-3395; Powers et al. (1996) J. Infect. Dis. 173:1014-1018).
It is a primary object of the invention to provide a method for boosting in an adult subject an immune response against meningococcal capsular antigen. The method generally entails the steps of (a) administering a first vaccine composition to an adult subject in order to elicit an immune response against a meningococcal species, and (b) administering a second vaccine composition to said adult subject in order to boost the anti-meningococcal response. The first vaccine composition comprises a meningococcal oligosaccharide conjugated to a carrier molecule, wherein the composition is administered in an amount sufficient to elicit an anti-meningococcal immune response, and said immune response is boostable upon revaccination with a second meningococcal vaccine composition. The second vaccine composition is administered to the subject after serum anti-meningococcal antibody concentration induced by the first vaccine composition have declined to subprotective levels.
It is also an object of the invention to provide a use of a first and second meningococcal polysaccharide or oligosaccharide composition in the preparation of a medicament. The first composition comprises a meningococcal oligosaccharide conjugated to a carrier molecule, and is administered in an amount sufficient to elicit an anti-meningococcal immune response which is boostable upon re-vaccination with a second meningococcal vaccine composition. The second composition comprises a meningococcal polysaccharide or oligosaccharide immunogen, and is administered to the subject after serum anti-meningococcal antibody concentrations induced by the first vaccine composition have declined to sub-protective levels.
It is an advantage of the present invention that the methods and uses can be employed in an anti-meningococcal vaccination protocol which avoids problems associated with induction of immunological tolerance to meningococcal immunogens as seen with prior vaccination strategies.
It is also a feature of the present invention that a wide variety of commonly available anti-meningococcal capsular oligosaccharide or polysaccharide glycoconjugates may be used as the immunogen in the first vaccine composition.
Additional objects, advantages and novel features of the invention will be set forth in part in the description which follows, and in part will become apparent to those skilled in the art upon examination of the following, or may be learned by practice of the invention.